Diabetes Care Volume 44, October 2021 2231

Historical HbA1c Values May Marcus Lind,1,2 Henrik Imberg,3

Ruth L. Coleman,4 Olle Nerman,3 and
Explain the Type 2 Diabetes Rury R. Holman4

Legacy Effect: UKPDS 88

Diabetes Care 2021;44:2231–2237 | https://doi.org/10.2337/dc20-2439

OBJECTIVE
Type 2 diabetes all-cause mortality (ACM) and myocardial infarction (MI) glyce-
mic legacy effects have not been explained. We examined their relationships with
prior individual HbA1c values and explored the potential impact of instituting ear-
lier, compared with delayed, glucose-lowering therapy.

RESEARCH DESIGN AND METHODS

Twenty-year ACM and MI hazard functions were estimated from diagnosis of
type 2 diabetes in 3,802 UK Prospective Diabetes Study participants. Impact of
HbA1c values over time was analyzed by weighting them according to their influ-
ence on downstream ACM and MI risks.

RESULTS 1
Institute of Medicine, Sahlgrenska Academy,
Hazard ratios for a one percentage unit higher HbA1c for ACM were 1.08 (95% CI University of Gothenburg, Gothenburg, Sweden
2
1.07–1.09), 1.18 (1.15–1.21), and 1.36 (1.30–1.42) at 5, 10, and 20 years, respec- Department of Medicine, NU-Hospital Group,
tively, and for MI was 1.13 (1.11–1.15) at 5 years, increasing to 1.31 (1.25–1.36) Uddevalla, Sweden
3
Department of Mathematical Sciences,
at 20 years. Imposing a one percentage unit lower HbA1c from diagnosis gener- Chalmers University of Technology and
ated an 18.8% (95% CI 21.1–16.0) ACM risk reduction 10–15 years later, whereas University of Gothenburg, Gothenburg, Sweden

EFFECTS OF EARLIER GLYCEMIC CONTROL

4
delaying this reduction until 10 years after diagnosis showed a sevenfold lower Diabetes Trials Unit, Radcliffe Department of
2.7% (3.1–2.3) risk reduction. Corresponding MI risk reductions were 19.7% Medicine, University of Oxford, Oxford, U.K.
(22.4–16.5) when lowering HbA1c at diagnosis, and threefold lower 6.5% Corresponding author: Marcus Lind, marcus.
lind@gu.se
(7.4–5.3%) when imposed 10 years later.
Received 2 October 2020 and accepted 3 May
CONCLUSIONS 2021

The glycemic legacy effects seen in type 2 diabetes are explained largely by histor-
ical HbA1c values having a greater impact than recent values on clinical outcomes.
Early detection of diabetes and intensive glucose control from the time of diagno-
sis is essential to maximize reduction of the long-term risk of glycemic
complications.
The UK Prospective Diabetes Study (UKPDS) demonstrated that intensive glycemic
control, which achieved 0.9% lower HbA1c levels on average compared with con-
ventional glycemic control, lowered the risk of microvascular complications in
patients with type 2 diabetes (T2D) (1). The risks for all-cause mortality (ACM) and
myocardial infarction (MI) were not reduced, although the 16% numerical MI risk
reduction was borderline statistically significant (P 5 0.052). A subsequent patient-
level meta-analysis of Action to Control Cardiovascular Risk in Diabetes (ACCORD),
Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled
This article contains supplementary material online
at https://doi.org/10.2337/figshare.14575173.
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2225.
2232 Historical HbA1c Values Explain Legacy Effect
Evaluation (ADVANCE), UKPDS, and Vet-
erans Affairs Diabetes Trial (VADT),
however, confirmed a 15% MI risk
reduction for a 0.88% lower HbA1c (2).
Ten-year posttrial monitoring of sur-
viving UKPDS participants, with virtually
no glycemic differences between those
randomized previously to intensive or
conventional glycemic strategies, revealed
relative risk reductions of 16% for ACM
(P 5 0.007) and 15% for MI (P 5 0.01)
(3). These findings, suggesting there is
a “legacy” effect conferred by earlier
improved glycemic control with increas-
ingly beneficial effects on ACM and MI
risks over time (3), have helped influ-
ence guidelines to advocate early more
intensive postdiagnosis glucose-lowering
therapy. Many patients, however, still
do not reach their glycemic targets
(4–6). Because significant resources are
required to promote early diabetes
detection (e.g., screening large popula-
tions) and to optimize glycemic control
after diagnosis, it is essential for care
givers, patients, and decision makers to
know to what extent early intensive
glycemic control can reduce the risk of
long-term complications.
In this UKPDS analysis, we examine
the degree to which relationships
between individual historical HbA1c
values over time and downstream
risks of ACM and MI may explain the
T2D glycemic legacy effect.
RESEARCH DESIGN AND METHODS
Population
The UKPDS design and results have been
described previously (1,3,7,8). Briefly,
participants were stratified by ideal body
weight (<120% vs. $120%) (8), with
nonoverweight participants assigned ran-
domly to an intensive (insulin or sulfonyl-
urea) or conventional (diet) glycemic
management strategy. Overweight par-
ticipants assigned to the intensive
glycemic strategy could also be allo-
cated to metformin (8). The aim for all
participants was a fasting plasma glucose
<6.0 mmol/L, with second-line glucose-
lowering therapy permitted only if fast-
ing plasma glucose values became >15
mmol/L or unacceptable signs of hyper-
glycemia developed.
After UKPDS closeout, all surviving
participants entered a 10-year posttrial
monitoring period and were returned to
routine care, with no attempt made to
maintain trial-allocated treatment regi-
mens (3). They were seen annually at
UKPDS centers for the first 5 years with
collection of standardized data, includ-
ing HbA1c. Thereafter, participants were
monitored remotely by means of annual
participant- and general practitioner-
completed questionnaires.
In this analysis, only those assigned
originally to an intensive glycemic strat-
egy with a sulfonylurea or insulin, or to
a conventional glycemic strategy with
diet, were evaluated. HbA1c values were
measured annually in the UKPDS. Partic-
ipants were excluded if they had a miss-
ing baseline HbA1c value or did not
have at least one follow-up HbA1c value
recorded during the 2 years preceding
ACM or MI. HbA1c values, measured as
% (7), have been converted to mmol/
mol according to guidelines (9).
Relationship of Historical HbA1c
Values to Downstream ACM and MI
Risks
Time-to-event analysis of diabetes com-
plications and HbA1c is commonly per-
formed using baseline or updated mean
HbA1c values (10–13). However, none of
these HbA1c metrics consider how HbA1c
values, measured at different historical
time points, may vary in their individ-
ual contribution to the downstream
risk of diabetes-related complications.
Accordingly, we used a model in which
historical HbA1c values were weighted
unequally to allow for different risk
contributions at each time point. This
was done using a multivariable regres-
sion model where optimal weights for
historical HbA1c values were estimated
simultaneously with the effect of the
influence weighted HbA1c variable and
coefficients for other covariates (14,15).
The overall temporal relationship of
HbA1c with ACM and MI was investi-
gated by estimating the degree to
which the instantaneous risk (hazard)
of ACM and MI at 15 and 20 years
after diagnosis could be ascribed to
HbA1c values measured at previous time
points.
ACM and MI Hazard Ratios in
Relation to HbA1c
The impact of HbA1c values on diabe-
tes-related complications has commonly
been estimated by calculating hazard
ratios (HRs) in relation to a one percent-
age unit (11 mmol/mol) difference in
Diabetes Care Volume 44, October 2021
HbA1c (10,13–15). We estimated ACM
and MI HRs at 5, 10, 15, and 20 years
after diagnosis of diabetes, assuming a
one percentage unit (11 mmol/mol)
higher HbA1c from diagnosis onward. To
further understand the impact of histor-
ical HbA1c levels on downstream ACM
and MI risks (legacy effects), we also
estimated ACM and MI HRs at 10–20
years after diagnosis in relation to a one
percentage unit (11 mmol/mol) lower
HbA1c, imposed at diagnosis of diabetes
or delayed until 5 or 10 years later.
These estimations were repeated for
HbA1c decrements of 0.5% (5.5 mmol/
mol) and 2.0% (22 mmol/mol).
ACM and MI Relative Risks Relating
to Historical HbA1c Values
To study how prior HbA1c values might
influence the incidence of downstream
ACM and MI over a longer time period,
we estimated ACM and MI relative risks
at 0–10, 10–15, and 10–20 years after
diagnosis when a lower HbA1c was imposed
immediately compared with delaying this
until 5 or 10 years later.
Impact of UKPDS Randomized
Glycemic Strategies
To evaluate whether factors other than
glycemic control might explain differ-
ences in outcomes, we investigated the
extent to which assignment to an inten-
sive or conventional glycemic control
strategy, irrespective of achieved HbA1c
values, affected the incidence of ACM
and MI.
Statistical Analyses
We used a multivariable Poisson regres-
sion model that included HbA1c, age,
sex, and diabetes duration with the
total follow-up period for each patient
subdivided into small intervals of 0.2
years, for each of which a constant haz-
ard was assumed. HbA1c was included
in the model as a time-dependent
weighted integral of all prior HbA1c val-
ues, with values weighted unequally to
allow for a potential different risk contri-
bution at each time point. The influence-
weighted HbA1c variable was computed
by first creating a continuous HbA1c curve
using linear interpolation between observed
HbA1c values, which was then weighted by
a piecewise exponential weight function
with one knot. The optimal HbA1c weight
function parameters were estimated simul-
taneously with the coefficients of the
care.diabetesjournals.org
covariates in the model using maximum
likelihood estimation.
Likelihood ratio tests were used to
assess the significance of individual
model parameters, with corresponding
CIs computed by test inversion (16). Esti-
mates and CIs for influence-weighted
HbA1c HRs at various follow-up times
and for relative risks associated with
imposed immediate or delayed HbA1c
reductions were computed from the cor-
responding regression coefficient, fixing
the HbA1c weight function parameters at
their estimated values. Model fit was
assessed by comparing observed and
expected event numbers for various age
categories and follow-up times. Addi-
tional model and statistical methodology
details can be found here (14,15) and in
the Supplementary Material (additional
statistical analysis details).
Data and Resource Availability
Data may be accessed after a written
research proposal and support from inves-
tigators and upon request and an appro-
priate data transfer agreement is in place.
RESULTS
Patient Characteristics
Requisite UKPDS data were available for
3,802 participants with 775 ACM events
and for 3,219 participants with 662 MI
events. Their mean age at diagnosis of
diabetes was 53.3 (SD 8.6) years, and
38.8% were women. For ACM and MI
analyses, there were 3,321 (87%) and
3,219 (85%) participants, respectively,
monitored for >5 years. The number of
participants included in the analyses
Table 1—HRs for ACM and MI per one-half, one, and two percentage unit (5.5, 11, and 22 mmol/mol) higher HbA1c (%) values
over the first 5, 10, 15, and 20 years after the diagnosis of T2D
HR (95% CI) per 0.5 percentage
Years after diagnosis units higher
ACM
5 1.04
10 1.09
15 1.13
20 1.17
MI
5 1.06
10 1.10
15 1.13
20 1.14
All HRs are statistically significant with P < 0.0001. The hazard ratio per z-units increase in HbA1c during t years after diagnosis is given by
Eq. 5 in the Supplementary Material. The model coefficients of the HbA1c weight function and covariates included in the model are presented
in Supplementary Table 1.
with follow-up of >10 and 15 years for
ACM were 2,742 (72%) and 1,299
(34%), respectively, and for MI were 2,544
(67%) and 1,156 (30%), respectively.
ACM and MI HRs in Relation to HbA1c
Higher HbA1c values were associated
significantly with both higher ACM and
MI risks (both P < 0.0001). HRs for
ACM and MI in relation to imposed
0.5% (5 mmol/mol), 1% (11 mmol/mol),
and 2% (22 mmol/mol) higher HbA1c
values during the first 5, 10, 15, or 20
years after the diagnosis of diabetes are
presented in Table 1. Each 1% (11
mmol/mol) higher HbA1c was related to
steadily higher HRs over time for ACM
and MI, suggesting increasingly harmful
effects of earlier hyperglycemia. HRs for
ACM per 1% (11 mmol/mol) higher
HbA1c value were 1.08 (95% CI 1.07–1.09),
1.18 (1.15–1.21), and 1.36 (1.30–1.42) at
5, 10, and 20 years of follow-up, respec-
tively, while MI HRs increased from 1.13
(1.11–1.15) at 5 years to 1.31 (1.25–1.36)
at 20 years.
Imposing a one percentage unit (11
mmol/mol) lower HbA1c from the diag-
nosis of diabetes significantly lowered
the instantaneous risk (hazard) of ACM
or MI events 15 and 20 years later,
compared with reducing HbA1c by the
same amount from 10 years after diag-
nosis (Fig. 1). ACM HRs (95% CI) at 15
and 20 years after diagnosis when
reducing HbA1c from diagnosis, compared
with from 10 years after diagnosis, were,
respectively, 0.78 (0.76–0.81) vs. 0.93
(0.92–0.94) and 0.73 (0.70–0.77) vs. 0.84
(0.82–0.87). Corresponding MI HRs were,
respectively, 0.79 (0.76–0.82) vs. 0.88
HR (95% CI) per 1 percentage
units higher
(1.03–1.04) 1.08 (1.07–1.09)
(1.07–1.10) 1.18 (1.15–1.21)
(1.11–1.15) 1.28 (1.23–1.32)
(1.14–1.19) 1.36 (1.30–1.42)
(1.05–1.07) 1.13 (1.11–1.15)
(1.08–1.12) 1.22 (1.17–1.25)
(1.10–1.15) 1.27 (1.22–1.32)
(1.12–1.17) 1.31 (1.25–1.36)
Lind and Associates 2233
(0.87–0.90) and 0.76 (0.73–0.80) vs.
0.82 (0.80–0.85). HRs calculated when
HbA1c lowering was delayed approached
those of immediate HbA1c lowering
somewhat more rapidly for MI than for
ACM (Fig. 1). Similar relationships over
time were found for ACM and MI when
HbA1c was lowered by one-half or two
percentage units (Supplementary Figs. 2
and 3).
Relative Risks of ACM and MI 10–20
Years After Diagnosis in Relation to
Early or Delayed Imposed Lowering
of HbA1c
To study glucose-lowering legacy effects
over longer time periods, we estimated
the effect of imposing immediate or
delayed HbA1c reductions on ACM and
MI risks between 0–10, 10–15, and
10–20 years after diagnosis. The esti-
mated ACM relative risk reduction was
18.8% (95% CI 21.1–16.0) at 10–15
years per one percentage unit lower
HbA1c when imposed from diagnosis,
but sevenfold smaller at 2.7% (3.1–2.3)
when imposed 10 years after diagnosis.
The corresponding MI estimates showed
a threefold smaller relative risk reduction
comparing delayed with immediate
imposition of a lower HbA1c (Table 2).
For the period 10–20 years after diag-
nosis, delayed compared with immedi-
ate imposition HbA1c lowering by one
percentage unit (11 mmol/mol) resulted
in an approximately threefold smaller
ACM relative risk reduction and a two-
fold smaller MI relative risk reduction
(Table 2). Similar legacy effects for ACM
and MI risks were seen with imposed
HR (95% CI) per 2 percentage
units higher
1.16 (1.14–1.19)
1.40 (1.33–1.47)
1.64 (1.51–1.75)
1.86 (1.68–2.03)
1.28 (1.22–1.33)
1.48 (1.38–1.57)
1.62 (1.49–1.75)
1.71 (1.55–1.86)
2234 Historical HbA1c Values Explain Legacy Effect
Figure 1—Time-dependent HRs for all cause-mortality (left) and myocardial infarction (right) from 0 to 20 years after diagnosis of type 2 diabetes,
assuming a one percentage unit lower HbA1c from diagnosis (green dotted lines), and when the same degree of HbA1c lowering was imposed from
5 years (blue dashed lines), and from 10 years (red solid lines) after diagnosis. The shaded regions represent 95% confidence limits. HRs were cal-
culated according to Eq. 6 in the Supplementary Material.
0.5% and 2.0% lower HbA1c values
(Supplementary Table 2).
Relationship of Historical HbA1c
Values to Downstream ACM and MI
Risks
The overall temporal relationships of
HbA1c with ACM and MI are shown in
Fig. 2. HbA1c values measured during
the first 10 years after diagnosis contrib-
uted to 69% (95% CI 60–75) of the
HbA1c total effect on ACM risk 15 years
after diagnosis and to 45% (33–54) at
20 years (Fig. 2). The corresponding MI
estimates were 49% (95% CI 37–56) and
27% (16–35).
Impact of Age, Sex, and Assigned
Glycemic Control Strategy
Older age and male sex were associated
significantly (both P < 0.0001) with
increased ACM and MI risks (Supplementary
Table 1). When HbA1c was included in the
model, the glycemic control strategy assign-
ment (intensive versus conventional) effect
was attenuated and not associated with
ACM (P 5 0.15) or MI (P 5 0.07).
Model Checks
Details of the final model estimated
parameters, including coefficients of the
HbA1c weight function, are provided in
Supplementary Table 1. Several model
checks were performed, with no lack-
of-fit detected. The model-predicted
cumulative number of UKPDS participants
experiencing an ACM or MI event was
similar to that observed (Supplementary Fig.
4). A sensitivity analysis to assess the impact
of baseline HbA1c, which excluded HbA1c val-
ues and deaths during the first 4 years after
diagnosis, showed similar time associations
between HbA1c and ACM. Similar patterns
were also seen when an interaction term for
time and HbA1c was included in the model.
CONCLUSIONS
Principal Findings
In this analysis of the UKPDS and its
posttrial monitoring period, we found
that historical HbA1c values were associ-
ated with strong legacy effects for the
downstream incidence of ACM and MI.
Analyses exploring the impact of delay-
ing the imposition of a 1% lower HbA1c
until 10 years after diagnosis of diabe-
tes, compared with doing this immedi-
ately, showed a sevenfold lower risk
reduction for ACM at 10–15 years. At
10–20 years after diagnosis, the risk of
death was reduced by threefold when
HbA1c was lowered from diagnosis. Sim-
ilar time-dependent effects were observed
for MI, but HbA1c legacy effects were
numerically greater for ACM than MI. The
impact on ACM and MI risks of delaying
imposition of improved glycemic control
after the diagnosis of diabetes increased
steadily with time. Thus, a one percentage
unit (11 mmol/mol) higher HbA1c level
was associated with an 8% greater ACM
Diabetes Care Volume 44, October 2021
risk at 5 years, increasing to 36% at 20
years. The risks for ACM and MI were cap-
tured by HbA1c, whereas the assigned gly-
cemic strategy group was not significant
when HbA1c was included in the model.
This finding strongly supports the fact that
the long-term ACM and MI risk reductions
seen in the UKPDS intensive glycemic
strategy group are driven by the early
introduction of improved glycemic control
(1,3). The somewhat stronger legacy effect
we see for ACM, compared with MI,
reflects the increased ACM risk reduction
from 6% to 13% during UKPDS posttrial
monitoring, while the degree of MI risk
reduction was essentially unchanged (16%
vs. 15%) (3).
Other Studies
The existence of a strong legacy effect
of earlier glycemic control on cardiovas-
cular disease is supported by findings
from studies of patients with type 1 dia-
betes. In the Epidemiology of Diabetes
Interventions and Complications (EDIC)
follow-up of the Diabetes Control and
Complications Trial (DCCT) study, partici-
pants previously assigned to intensive
glycemic therapy had fewer cardiovas-
cular disease events, even though the
glycemic difference between the inten-
sive and conventional groups was not
maintained (17,18). ACM and MI
reductions were not seen with inten-
sive glycemic therapy in any of the
three large-scale glucose-lowering
care.diabetesjournals.org Lind and Associates 2235

Table 2—Estimated relative risks of ACM and MI between 0–10, 10–15, and 10–20 years after diagnosis assuming a one
percentage unit (11 mmol/mol) lower HbA1c from diagnosis, and when the same HbA1c lowering was imposed from 5 and
from 10 years after diagnosis
Years after diagnosis HbA1c lowered at diagnosis HbA1c lowered 5 years after diagnosis HbA1c lowered 10 years after diagnosis
ACM
0–10 0.928 (0.919–0.939) 0.987 (0.985–0.989) 1.00
10–15 0.812 (0.789–0.840) 0.885 (0.870–0.902) 0.973 (0.969–0.977)
10–20 0.785 (0.758–0.815) 0.848 (0.829–0.871) 0.928 (0.919–0.939)
MI
0–10 0.893 (0.877–0.911) 0.968 (0.963–0.973) 1.00
10–15 0.803 (0.776–0.835) 0.851 (0.830–0.876) 0.935 (0.926–0.947)
10–20 0.788 (0.760–0.823) 0.826 (0.803–0.855) 0.893 (0.877–0.911)
Data are presented as relative risk (95% CI) per one percentage unit lower HbA1c. The relative risk of an event in a time interval 0–10, 10–15,
or 10–20 years after diagnosis was calculated according to Eq. 11 in the Supplementary Material.

studies performed over 3–5 years in
patients with generally long-standing
T2D (19–21). This may reflect the ini-
tially smaller risk reductions with
improved HbA1c or the late introduc-
tion of improved glycemic control in
patients with diabetes of long dura-
tion. Minimizing hyperglycemia plays a
major role in reducing the risk of diabetic
complications, particularly microvascular
complications (1,3,8), while other glu-
cose-lowering drugs, such as metformin,
glucagon-like peptide 1 (GLP-1) receptor
analogs, and sodium–glucose cotrans-
porter 2 inhibitors, likely also act via
additional nonglucose-lowering mecha-
nisms to reduce ACM and MI risks
(8,22,23). Nonetheless, while the risks of
MI and death have reduced over time,
these remain substantially higher for
people with T2D (24,25).
Explanations and Interpretations
The legacy effect of earlier hyperglyce-
mia on diabetic complications appears
to explain the increasing impact of his-
torical HbA1c values on ACM and MI
risks over time. Legacy effects in T2D
and “metabolic memory” in type 1 dia-
betes have been the subject of much
debate (3,17,26–29). Certain pathways
associated with diabetes complications
may be active later but initiated from
earlier increases in glucose, where reac-
tive oxygen species have been proposed
to play an essential role (26,30). The
reason legacy effects are somewhat
greater for ACM than MI is speculative.
It is possible that to some extent, death
may occur in a time-delayed fashion
from several diabetes-related complica-
tions (including MI), a fact that may
explain how HbA1c affects death and MI
with time. Early hyperglycemia leading
to nephropathy, initiating processes increas-
ing future risks of ACM and MI, including
hypertension, altered lipid metabolism, and
inflammatory processes, may also be a
major contributor (31,32). In multiple stud-
ies, renal complications have been major
risk factors for future cardiovascular disease
and mortality (13,31–33).
Implications
Although early more intensive glycemic
control in UKPDS participants with
newly diagnosed T2D has shown ACM

Figure 2—Contribution of historical HbA1c values to their impact on the instantaneous risk (hazard) of all-cause mortality (left) and myocardial
infarction (right) at 15 years (red solid lines) and 20 years (blue dashed lines) after diagnosis. The legacy effect of historical HbA1c values on diabe-
tes complications was more pronounced for ACM than for MI. The shaded regions represent 95% confidence limits. Details on the calculations
may be found in Eq. 7 in the Supplementary Material.
2236 Historical HbA1c Values Explain Legacy Effect
and MI risk reductions in the longer-
term, associations with individual histor-
ical HbA1c values and their long-term
effects have not been studied. Here we
show that imposing a lower HbA1c
immediately after the diagnosis of T2D
is associated with severalfold greater
risk reductions in ACM and MI 10–20
years later compared with delayed
HbA1c lowering. T2D is a worldwide epi-
demic affecting >463 million individuals
and causing a large proportion of severe
renal, visual, and cardiovascular disease
events as well as amputations and
shorter life expectancy (34). In addition,
many people have undetected diabetes
(34). Our results imply that societies
should focus even more on early T2D
detection and glucose optimization.
Moreover, programs in both children
and adults without diabetes could pre-
vent or delay diabetes onset and
thereby minimize glycemic exposure at
an even earlier time period.
Guidelines today recommend screen-
ing high risk groups (e.g., obese indi-
viduals and first-degree relatives of
individuals with T2D) (4,5), but few
structural programs exist in many
countries. If T2D remains undetected,
glucose levels can increase over many
years without symptoms but with ele-
vated HbA1c values that are associ-
ated with greatly increased risk, as
we have shown here; for example, a
2% (22 mmol/mol) higher HbA1c
increases ACM risk by 40% after 10
years and by 86% after 20 years.
Another implication is that glycemic
control contributes more to risk of ACM
and MI than previously thought. Our
study found an ACM risk increase of
>30% at 20 years per unit HbA1c
increase compared with 10–20% in pre-
vious studies (10–13). The difference is
due to the increasing effects over time,
which likely will increase even more for
many patients over a lifetime horizon.
Besides the need for early detection of
diabetes and glycemic optimization, our
findings support the need for strict gly-
cemic control when treating people
with T2D in clinical practice. Effects of
glucose-lowering treatments in cardio-
vascular outcome trials have likely
underestimated the effects of glycemic
control because the beneficial effects,
according to the current results,
increase over at least 15–20 years and
thus far beyond the duration of most
studies, which have generally been 3–5
years (19–23,28,29). The increasing and
larger risk reductions seen here over
time need to be considered when mak-
ing treatment decisions in clinical prac-
tice, writing guidelines, and performing
health care economic analyses.
These results are also of interest in
light of the current coronavirus disease
2019 pandemic. Individuals with T2D
with a high mortality risk after coronavi-
rus disease 2019 infection are generally
those with advanced diabetes complica-
tions (35,36). To help minimize such
risks in future viral epidemics, our find-
ings highlight the crucial need for early
implementation of intensive glycemic
control in people with newly diagnosed
T2D to reduce end-organ damage.
Strengths and Limitations
Strengths of our study include the
UKPDS long-term follow-up with detailed
HbA1c and adjudicated complication
data. Also, participants were monitored
from the diagnosis of T2D, which is
essential to capture as much information
as possible on early hyperglycemic
effects. The model we used has previ-
ously shown a better fit than traditional
models and variables used for describing
HbA1c in relation to diabetic complica-
tions (10,14,15). Although it shows a
good fit here, we cannot exclude resid-
ual confounding due to the study’s
observational nature. In particular, partial
confounding may exist between the
studied HbA1c variable, which varies non-
linearly with time since diagnosis, and
nonlinear effects of diabetes duration.
None of the conducted sensitivity analy-
ses, however, revealed any such pat-
terns. Because the current analyses
focused on the relative impact of histori-
cal HbA1c values, we did not evaluate
risk factors other than age, sex, and
treatment group. Moreover, it should be
noted that healthy living habits, which
may be associated with improved glyce-
mic control and were not controlled for
in the current analysis, can also influence
the risk of MI and mortality. For future
estimations of the probability of ACM or
MI for individuals, it will be essential to
include other risk factors and covariates.
However, HbA1c is already known to be
an independent risk factor for MI and
ACM, as shown in multiple studies,
including the UKPDS (11–13). In the
Diabetes Care Volume 44, October 2021
current study, intraindividual HbA1c val-
ues (i.e., for each participant) were eval-
uated to determine their relative
contributions over time to MI and ACM.
While it would be of interest to deter-
mine and also adjust for time-dependent
effects of other risk factors (smoking,
weight, blood pressure, and lipid pro-
files), they did not vary greatly over time
in UKPDS, and such analyses would be
complex to perform.
The use of statins and renin-angioten-
sin-aldosterone system inhibitors in UKPDS
were confined primarily to the posttrial
monitoring period. It is possible that by
reducing overall cardiovascular risk, they
might to some extent influence the effect
ascribed to historical HbA1c values but
not fundamentally change the relation-
ship between HbA1c and complications.
In conclusion, the adverse effects of
HbA1c on ACM and MI increase over
time. Strong HbA1c legacy effects exist
for both of these outcomes but appear
greater for ACM. Given these large leg-
acy effects, early detection of T2D
(screening) and glycemic optimization
needs greater emphasis in guidelines,
by health care providers, and in clinical
practice to more effectively prevent
long-term complications and achieve a
more normal life-expectancy for people
with T2D.
Acknowledgments. The authors want to
thank all participating sites and participants
for making the UKPDS trial possible. The
authors thank Anders Od
en (Chalmers Univer-
sity of Technology) for important contribu-
tions to the current work.
Funding. This study was supported by the
Swedish State (ALF grant). R.R.H. is an Emeri-
tus National Institute for Health Research
Senior Investigator.
Duality of Interest. M.L. has received
research grants from DexCom and Novo Nor-
disk and been a consultant for AstraZeneca,
Boehringer Ingelheim, DexCom, Eli Lilly, MSD,
and Novo Nordisk. R.R.H. reports research
support from AstraZeneca, Bayer, and Merck
Sharp & Dohme, and personal fees from Anji
Pharmacueticals, Bayer, Intarcia, Merck Sharp
& Dohme, Novartis, and Novo Nordisk. No
other potential conflicts of interest relevant
to this article were reported.
Author Contributions. M.L. wrote a first
draft of the manuscript. M.L., H.I., R.L.C.,
O.N., and R.R.H. were involved in analyses
and interpretations of data and revising the
manuscript. M.L. and R.R.H. are the guaran-
tors of this work and, as such, had full access
to all the data in the study and take responsi-
bility for the integrity of the data and the
accuracy of the data analysis.
care.diabetesjournals.org
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